APP/ABeta chemistry in transgenic, familial and sporadic AD

描述(申请人提供)：阿尔茨海默病(AD)是一种痴呆症，在美国有400万老年人受到影响。这种毁灭性的神经退行性疾病影响了4%的65岁人群和多达40%的85岁人群，每年造成约800亿美元的损失。由于寿命的显著增长，预计到2050年，阿尔茨海默病患者的数量将增加两倍。因此，迫切需要有效的治疗干预措施，以预防AD或推迟发病年龄或改变这种痴呆的病程。人类AD基因转基因(TG)小鼠的建立为研究AD的发病机制和治疗提供了重要工具。我们的目标是通过确定TG动物淀粉样蛋白与人类AD患者中沉积的淀粉样蛋白之间的生化相似程度，更好地了解TG小鼠模型的优点和局限性。在几种TG动物结构中产生的淀粉样蛋白表达大的淀粉样前体分子和关键的蛋白分解处理酶早老素的突变，将被提纯并进行化学表征，以确定与人类散发性和家族性AD患者的淀粉样蛋白的组成和结构。Tg小鼠和人类AD患者在抗Abeta免疫后残留的可溶和沉积的淀粉样蛋白将使用相同的化学技术进行检测，以评估免疫对淀粉样蛋白动力学和毒性的影响。这项研究将有助于准确解释TG小鼠的实验结果，并将有助于在分子水平上阐明抗Aβ免疫的直接和间接影响。完全了解TG小鼠的表型和对实验性治疗干预的反应将使新的结果能够以最小的延迟和最大的疗效和安全性信心应用于人类AD患者。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a dementia that affects 4 million elderly individuals in the USA. This devastating neurodegenerative disorder strikes 4% of individuals at 65 years of age and as many as 40% of those at age 85 at a cost of about 80 billion dollars annually. Due to an impressive increase in longevity there is a projected tripling in the number of AD dementia cases by the year 2050. Therefore, there is an urgent need for effective therapeutic interventions that may prevent AD or delay the age of onset or alter the course of this dementia. The creation of transgenic (tg) mice expressing human AD genes has provided vital tools to investigate both the pathogenesis and treatment of this dementia. Our goal is to better understand the strengths and limitations of tg mice models by determining the degree of biochemical similarities existing between tg animal amyloid and that deposited in human AD patients. Amyloid produced in several tg animal constructs that express mutations in the large amyloid precursor molecule and the key proteolytic processing enzyme presenilin will be purified and chemically characterized to determine composition and structure in comparison to human sporadic and familial AD patient amyloid. Soluble and deposited amyloid remaining after anti-Abeta immunization of tg mice and human AD patients will be examined using the same chemical techniques to assess the effects of immunization on amyloid dynamics and toxicity. This study will aid in the accurate interpretation of tg mouse experimental results and will help elucidate at the molecular level the direct and indirect effects of anti-Abeta immunization. A complete understanding of the tg mice phenotypes and responses to experimental therapeutic interventions will enable new results to be applied to human AD patients with minimum delay and maximum confidence in efficacy and safety.